Preterm birth disrupts nephron progenitor cell dynamics predisposing to renal disease.

Preterm birth is associated with a substantially increased lifetime risk of chronic kidney disease, yet the developmental mechanisms driving this association remain unclear. Using an established mouse model of preterm birth, we demonstrate that premature extrauterine life uncouples nephron progenitor cell (NPC) proliferation from differentiation. Although the nephrogenic window is transiently extended, it fails to rescue nephron endowment. Transcriptomic and biochemical analyses reveal that preterm NPCs mount an immediate stress response, marked by unfolded protein response and endoplasmic reticulum stress signatures. This molecular stress coincides with a disruption of the precise temporal dynamics required for efficient differentiation, predisposing to a permanent nephron deficit. Long-term follow-up confirms that these early defects manifest as adult glomerular hypertrophy, proteinuria, and tubular injury. Our findings identify stress-associated dysregulation of NPC dynamics as a central mechanism linking prematurity to lifelong kidney vulnerability, highlighting the perinatal period as a critical therapeutic window.